The RAIDER trial is looking at the issues regarding adaptive radiotherapy in bladder cancer. Using radiotherapy as a way of preserving the bladder has become increasingly accepted as an alternative to radical cystectomy but bladder radiotherapy is very challenging because the bladder can move and change shape on a daily basis. Over the last ten years we’ve been able to do imaging prior to each treatment and that has allowed us both to image guide the treatment but also to adapt the treatment to the patient’s individual circumstance on the day. The most common way of that is doing a process called “plan of the day”, where three individual plans are made of different sizes and the best one is selected for the patient each day. In the RAIDER trial we’re looking at what are the potential advantages of that approach and particularly taking that approach a stage forward to focus the main dose of the radiotherapy on the tumour bed and try to reduce the dose of radiotherapy to the rest of the bladder. Also looking at whether not using those techniques allows us to give a bigger total dose to the tumour, with the hope that that will improve tumour control rates going forward.
In the RAIDER trial, we undertook a randomised phase II study with two parallel different fractionation cohorts, the two common ways of giving the radiotherapy, one using 20 fractions and one using 32 fractions. We wanted to exclude an excessive rate of toxicity in those patients having a dose-escalation approach. We were trying to exclude a greater than 20% significant toxicity rate.
So we did a randomised trial between standard radiotherapy to the whole bladder, radiotherapy to a tumour boost with standard dose and then dose escalation. We’ve included 345 patients to ensure we had 57 evaluable patients in each of the dose escalated arms, and the patients had to have a late toxicity assessment without any recurrence between six to 18 months after treatment.
So what we showed in the study was that the adaption was very necessary. Less than 2% of patients had the same plan used throughout the treatment and about 60% of the fractions were adapted compared to the standard volume. The primary endpoint was this late toxicity endpoint and we showed that the rate of radiotherapy-related severe toxicity was very low in all the treatment groups and there was no evidence of any increase in the dose escalated group. In fact, there was one patient across the two fractionation cohorts in the escalated group who had severe toxicity which was the same as the other two groups. Even the rate of all grade 3 toxicity was less than our pre-set… the upper confidence limit of the estimates of those was below our pre-set threshold for excess toxicity. So we can do this quite successfully.
When we look at toxicity overall, the overall rates of toxicity were lower and less than we anticipated before we set up the study. There was no evidence of any increased toxicity for the dose escalated group and, in fact, in the adapted groups there was a tendency perhaps to have less toxicity, though we weren’t powered to formally detect that, particularly the urinary toxicity it looked like there was an interesting improvement.
The other important aspect is that we found that the overall control rate of the tumour was excellent. At the three month check 87% of patients had a biopsy-proven control of their cancer, of the people who had biopsies. We had a local disease-free survival rate of 79% in the two standard dose arms and 85% in the dose escalated group; that was a hazard ratio of 0.75, it wasn’t statistically significant but we were underpowered to detect a difference. The overall rate of control in those groups seemed to be somewhat better than our previous trial, the BC2001 trial, where that was similar to the invasive rate of control rather than all local control data. So I think overall showing that this sort of modern radiotherapy is getting excellent results when combined with chemotherapy.
Going forward, we can’t have any definitive proof about what to do, but it looks very promising for using these adaptive treatments to improve patient outcomes, and hopefully make bladder preservation even more acceptable as a modality of treatment.
What is your overall message for medical professionals?
Modern chemoradiotherapy using image-guided treatments and ideally with adaption gets very good results for patients with muscle-invasive bladder cancer and should be considered as an option for patients with T2 or T3 bladder cancer as an alternative to radical surgery, and patients go forward with a good quality of life and low toxicity rates.
